rs61750581

Variant names:

• chr12-6018581-A-G
• rs61750581
• NM_000552.5:c.4837T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP4_Moderate PM2_Supporting PS4_Supporting PP3

This summary comes from the ClinGen Evidence Repository: The c.4837T>C variant in VWF is a missense variant predicted to cause substitution of Serine by Proline at amino acid 1613 (p.Ser1613Pro). At least 1 patient (Patient 14 from PMID:38053262) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity as indicated by a VWF activity-to-antigen ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additional consistent phenotypes were also reported in the patient including a FVIII activity consistent with VWF antigen (ratio >0.7) (PP4_Moderate). This variant has been reported in one additional proband (Zimmerman program) with activity/antigen ratio <0.37, abnormal multimers, and normal platelet binding (PS4_Supporting). The computational predictor REVEL gives a score of 0.7, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate, PP3 and PM2_Supporting (VCEP specifications version 1.0.0; date of approval). LINK:https://erepo.genome.network/evrepo/ui/classification/CA114131/MONDO:0015628/081

• Frequency: Genomes: not found (cov: 31)
• Consequence: VWF NM_000552.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 O:1
• Conservation: PhyloP100: 3.61

Genes affected

VWF (HGNC:12726): (von Willebrand factor) This gene encodes a glycoprotein involved in hemostasis. The encoded preproprotein is proteolytically processed following assembly into large multimeric complexes. These complexes function in the adhesion of platelets to sites of vascular injury and the transport of various proteins in the blood. Mutations in this gene result in von Willebrand disease, an inherited bleeding disorder. An unprocessed pseudogene has been found on chromosome 22. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWF	NM_000552.5	c.4837T>C	p.Ser1613Pro	missense_variant	Exon 28 of 52	ENST00000261405.10	NP_000543.3
VWF	XM_047429501.1	c.4837T>C	p.Ser1613Pro	missense_variant	Exon 28 of 52		XP_047285457.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWF	ENST00000261405.10	c.4837T>C	p.Ser1613Pro	missense_variant	Exon 28 of 52	1	NM_000552.5	ENSP00000261405.5
VWF	ENST00000538635.5	n.421-24647T>C		intron_variant	Intron 5 of 5	4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Von Willebrand disease type 2A Pathogenic:1 Uncertain:1

May 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 04, 2025

ClinGen von Willebrand Disease Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.4837T>C variant in VWF is a missense variant predicted to cause substitution of Serine by Proline at amino acid 1613 (p.Ser1613Pro). At least 1 patient (Patient 14 from PMID: 38053262) with this variant displayed excessive mucocutaneous bleeding as well as laboratory phenotypes of very low VWF activity as indicated by a VWF activity-to-antigen ratio <0.7, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. Additional consistent phenotypes were also reported in the patient including a FVIII activity consistent with VWF antigen (ratio >0.7) (PP4_Moderate). This variant has been reported in one additional proband (Zimmerman program) with activity/antigen ratio <0.37, abnormal multimers, and normal platelet binding (PS4_Supporting). The computational predictor REVEL gives a score of 0.7, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). This variant is absent from gnomAD v4.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as VUS for autosomal recessive von Willebrand disease type 2A based on the ACMG/AMP criteria applied, as specified by the ClinGen VWD VCEP: PS4_Supporting, PP4_Moderate, PP3 and PM2_Supporting (VCEP specifications version 1.0.0; date of approval). -

not provided Other:1

-

Academic Unit of Haematology, University of Sheffield

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.46
MutPred		0.82		Gain of catalytic residue at G1609 (P = 0.0101);
MVP		0.89
MPC		0.90
ClinPred		0.92	D
GERP RS		2.3
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61750581; hg19: chr12-6127747;